The Dok-3/Grb2 Protein Signal Module Attenuates Lyn Kinase-dependent Activation of Syk Kinase in B Cell Antigen Receptor Microclusters

Lösing, Marion; Goldbeck, Ingo; Manno, Birgit; Oellerich, Thomas; Schnyder, Tim; Bohnenberger, Hanibal; Stork, Björn; Urlaub, Henning; Batista, Facundo D.; Wienands, Jürgen; Engelke, Michael

doi:10.1074/jbc.m112.406546

Cited by 20 publications

(29 citation statements)

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“…5). First, we considered the regulation of proximal B-cell receptor signaling, both positively by mutation or amplification of CD79B and CD79A (“CD79A/B”) and negatively by known inhibitors of B-cell receptor signaling in normal B cells, including LAPTM5, 17 LYN, 18 PTPN6, 18 GRB2, 19 PRKCD, 20 DGKZ, 21 SLA, 22 and MAP4K1 23 (Fig. 5, and Fig.…”

Section: Resultsmentioning

confidence: 99%

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Schmitz¹,

Wright

Huang³

et al. 2018

N Engl J Med

1,611

1,936

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BACKGROUND Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell–like [ABC], germinal-center B-cell–like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on “chronic active” B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.)

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Section: Resultsmentioning

confidence: 99%

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Schmitz¹,

Wright

Huang³

et al. 2018

N Engl J Med

1,611

1,936

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“…dedicator of cytokinesis 9 (Dock9), pinin‐interacting serine/arginine‐rich protein (PNISR), actin‐related protein 2/3 complex subunit 2 (ArpC2), and interestingly the BCR signaling subunit Igα (for details see Supporting Information Table 1). Among the B‐lymphoid SHIP ligands, Dok‐3 and its reported binding partner Grb2 represented possible membrane anchors because, firstly, Dok‐3 harbors a PH domain that tethers the protein to the inner leaflet of the plasma membrane, and secondly, the Dok‐3/Grb2 module has been described as negative regulator of BCR signaling .…”

Section: Resultsmentioning

confidence: 99%

The Dok‐3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor‐independent manner

et al. 2016

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The SH2 domain-containing inositol 5'-phosphatase (SHIP) plays a key role in preventing autoimmune phenomena by limiting antigen-mediated B cell activation. SHIP function is thought to require the dual engagement of the BCR and negative regulatory coreceptors as only the latter appear capable of recruiting SHIP from the cytosol to the plasma membrane by the virtue of phosphorylated immunoreceptor tyrosine-based inhibitory motifs. Here, we demonstrate a coreceptor-independent membrane recruitment and function of SHIP in B cells. In the absence of coreceptor ligation, SHIP translocates to sites of BCR activation through a concerted action of the protein adaptor unit Dok-3/Grb2 and phosphorylated BCR signaling components. Our data reveal auto-inhibitory SHIP activation by the activated BCR and suggest an unexpected negative-regulatory capacity of immunoreceptor tyrosine-based activation motifs in Igα and Igβ.

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“…Ultimately, Grb2 inhibits Btk-dependent phosphorylation of PLC-γ2. Although the precise mechanism is not clear, Grb2/Dok3 might interfere with the movement of BCR microcluster to gather the antigen-BCR complex (Schnyder et al 2011), and/or the formation of BCR signalosome, thereby inhibiting the activity of Lyn (Losing et al 2013). This leads to the attenuation of the activation of Syk, Btk, and PLC-γ2.…”

Section: Soce Regulatormentioning

confidence: 96%

Role of Calcium Signaling in B Cell Activation and Biology

Baba

Kurosaki

2015

Current Topics in Microbiology and Immunology

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Increase in intracellular levels of calcium ions (Ca2+) is one of the key triggering signals for the development of B cell response to the antigen. The diverse Ca2+ signals finely controlled by multiple factors participate in the regulation of gene expression, B cell development, and effector functions. B cell receptor (BCR)-initiated Ca2+ mobilization is sourced from two pathways: one is the release of Ca2+ from the intracellular stores, endoplasmic reticulum (ER), and other is the prolonged influx of extracellular Ca2+ induced by depleting the stores via store-operated calcium entry (SOCE) and calcium release-activated calcium (CRAC) channels. The identification of stromal interaction molecule 1(STIM1), the ER Ca2+ sensor, and Orai1, a key subunit of the CRAC channel pore, has now provided the tools to understand the mode of Ca2+ influx regulation and physiological relevance. Herein, we discuss our current understanding of the molecular mechanisms underlying BCR-triggered Ca2+ signaling as well as its contribution to the B cell biological processes and diseases.

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The Dok-3/Grb2 Protein Signal Module Attenuates Lyn Kinase-dependent Activation of Syk Kinase in B Cell Antigen Receptor Microclusters

Cited by 20 publications

References 50 publications

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

The Dok‐3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor‐independent manner

Role of Calcium Signaling in B Cell Activation and Biology

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